Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies using cultures of fetal rodents calvaria have indicated an important role for insulin-like growth factor-I (IGF-I) in the local control of bone formation. In this study, we have examined the expression of IGF-I in adult human osteoblast-like (hOB) cells. To detect very low levels and to distinguish between the two IGF-I mRNA transcripts Ea and Eb, which are formed by alternate splicing, we have used the reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of both Ea and Eb IGF-I mRNA transcripts were found in human liver and in placenta. However, neither Ea nor Eb IGF-I mRNA could be detected under basal conditions or after stimulation with growth hormone in normal hOB cells and two human osteosarcoma cell lines with osteoblastic properties, SaOS-2 and MG-63. We conclude that adult hOB cells do not synthesize IGF-I. Thus, in contrast to its crucial role as a local regulator of skeletal remodeling in fetal rodent bone, IGF-I does not appear to have this autocrine function in adult human bone.
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PMID:Adult human osteoblast-like cells do not express insulin-like growth factor-I. 812 49

The mechanisms involved in the mitogenic actions of insulin-like growth factor-I (IGF-I) on skeletal cells are at present unclear. We have investigated the role of glucose-6-phosphate dehydrogenase (G6PD) in this mechanism and provide strong evidence that stimulation of G6PD activity is required for the growth promoting activities of IGF-I. IGF-I (10 ng/ml) significantly elevated G6PD activity in MG-63 human osteosarcoma cells within 30 min which preceded the IGF-I induced DNA synthesis in these cells. Inhibition of G6PD activity by epiandrosterone decreased DNA synthesis in IGF-I stimulated MG-63 cells but this was partly overcome by the addition of a combination of the four deoxyribonucleosides. IGF-I did not cause a general increase in cell metabolism as succinate dehydrogenase and iso-citrate dehydrogenase activity were not altered. Although IGF-I caused a significant increase in lactate dehydrogenase activity this was not inhibited by epiandrosterone. The culture of metatarsals of 4-week-old rats with IGF-I (10 ng/ml) also stimulated G6PD activity in osteoblasts lining the metaphyseal trabeculae.
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PMID:Mitogenic action of insulin-like growth factor-I on human osteosarcoma MG-63 cells and rat osteoblasts maintained in situ: the role of glucose-6-phosphate dehydrogenase. 825 63

The 1,25-dihydroxyvitamin-D3-(calcitriol)-induced medium osteocalcin and cellular osteocalcin mRNA concentrations are increased in a dose-dependent and time-dependent manner by prior treatment of the human MG-63 osteosarcoma cells with insulin-like growth factor-I (IGF-I). In addition, IGF-I reverses the inhibitory effects of dexamethasone and enhances the effects of retinoic acid on osteocalcin synthesis. The stimulatory effect of IGF-I on osteocalcin synthesis is accompanied by stabilization of osteocalcin mRNA and a decrease of AP-1 binding to the osteocalcin promoter. The binding of the vitamin-D receptor (VDR) to its cognate response element is not affected by IGF-I. In contrast to its effects on osteocalcin synthesis, both baseline and calcitriol-stimulated alkaline phosphatase activities are decreased by IGF-I treatment. Furthermore, IGF-I has mitogenic effects on MG-63 cells. The proliferation of the cells and the levels of c-jun mRNA are greatly increased during IGF-I treatment. Calcitriol reduces or eliminates both these effects. The low concentrations of IGF-I used in this study suggest that IGF-I is an important normal regulator of the synthesis of osteocalcin, a bone calcium-binding protein participating in bone mineralization, by modulating the effects of steroid hormones on its synthesis.
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PMID:Insulin-like growth factor-1 modulates steroid hormone effects on osteocalcin synthesis in human MG-63 osteosarcoma cells. 828 40

Osteoblast-like UMR-106.01 rat osteosarcoma cells express high affinity growth hormone (GH) receptors (GHRs). Because osteoblasts secrete insulin-like growth factor binding protein-5 (IGFBP-5), we evaluated whether it also modulates GH binding and GHR expression in UMR cells. Human recombinant intact IGFBP-5 stimulated 125I-hGH binding in a dose-dependent manner (dose range 300-3000 ng/ml), inducing an increase to 193.6 +/- 2.1% of control binding at 3000 ng/ml (P < 0.001). Carboxy-truncated IGFBP-5 also stimulated GH binding but with less potency (125 +/- 2.7% of control at 3000 ng/ml, P < 0.01). GHRs identified by chemical crosslinking of 125I-hGH to cell monolayers increased after treatment with IGFBP-5 and decreased in response to insulin-like growth factor-I (IGF-I). GHR mRNA levels, as quantitated by a solution hybridization RNAse protection assay, increased up to 3 to 7-fold in a time-dependent manner by intact IGFBP-5 but not by carboxy-truncated IGFBP-5. An antiserum to IGFBP-5 reduced basal GH binding to 56.7 +/- 4.3% of control value at a concentration of 0.5% (P < 0.001), showing that IGFBP-5 produced by the cells is a strong regulator of GH binding. IGFBP-5 antiserum also decreased GH binding to 85.9 +/- 0.9% of IGFBP-5 stimulated value (P < 0.001), showing the specificity of IGFBP-5 stimulation. To determine whether the GHR upregulation was physiologically significant, cell proliferation was evaluated after coincubation of IGFBP-5 with low, non-stimulatory concentrations of GH. IGFBP-5 (1000 ng/ml) induced cell proliferation to 116.2 +/- 3.2% of control levels, and coincubation with hGH at 10 ng/ml induced an increase to 133.3 +/- 0.1% of control levels. We conclude that exogenous and endogenous IGFBP-5 upregulate GHR mRNA levels and GH binding and this interaction potentiates GH-stimulated mitogenesis in osteoblastic cells.
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PMID:Growth hormone receptor activity is stimulated by insulin-like growth factor binding protein 5 in rat osteosarcoma cells. 897 53

In this report, comparisons between molecular affinities and cellular proliferation activities have been made for insulin-like growth factor-I (IGF-I) and two IGF-I fusion proteins in order to evaluate fusion proteins as tools for receptor binding studies. Binding affinities and growth promoting effects of the N-terminal fusion Z-IGF-I and the C-terminal fusion IGF-I-Z, and native recombinant human IGF-I, were analyzed. Binding kinetic properties of the three IGF-I variants were analyzed using BIAcore kinetic interaction analysis testing for binding to both human IGF binding protein 1 (IGFBP-1) and a soluble form of the human IGF type I receptor extracellular domains (sIGF-IR). The growth promoting effects on SaOS-2 human osteosarcoma cells of the different fusion proteins were analyzed. A comparison of receptor binding affinities and growth promoting effects shows that the fusion protein receptor affinity does not correlate with proliferative potential. The IGF-I-Z fusion, with the lowest receptor affinity, shows similar proliferative potential to native IGF-I. However, the Z-IGF-I fusion protein, with twice the receptor affinity of IGF-I-Z, displays only about 70% of the IGF-I-Z growth promoting activity. Both IGF-I fusion proteins possess similar affinity to IGFBP-1. These results indicate that determinants other than the receptor affinity could be involved in the regulation of IGF-I proliferative action. This study demonstrates that ligand fusion proteins may be useful to study mechanisms of ligand induced receptor activation.
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PMID:Binding affinities of insulin-like growth factor-I (IGF-I) fusion proteins to IGF binding protein 1 and IGF-I receptor are not correlated with mitogenic activity. 937 65

The insulin-like growth factor-I receptor (IGF-IR) is involved in tumorigenesis. The aim of the present study was to investigate whether the IGF-IR is a physiological target for p53 in osteosarcoma cells. The p53-induced regulation of IGF-IR levels was studied in a tetracycline-regulated expression system. When expressed in Saos-2, osteosarcoma cells that lack p53, wild-type p53 decreased, whereas mutated p53 increased IGF-IR expression, and IGF-I-induced tyrosine phosphorylation of the IGF-IR. Similarly, wild-type p53 decreased IGF-I-induced tyrosine phosphorylation of IRS-1. A functional and physical interaction between p53 and Sp1, in the regulation of the IGF-R, was studied in osteosarcoma cells. Expression of p53 decreased IGF-IR promoter activity, whereas no effect on promoter activity was seen by Sp1 expressed alone. However, Sp1 counteracted the inhibitory effect of p53 on IGF-IR promoter activity in a dose-dependent manner. Furthermore, wild-type and mutated p53 were coimmunoprecipitated with Sp1, indicating a physical interaction between p53 and Sp1. In conclusion, p53 regulates IGF-IR expression, as reflected by a reduction in IGF-IR protein and a parallel reduction in IGF-I-induced tyrosine phosphorylation of the IGF-IR and IRS-1 in an osteosarcoma cell line. These data indicate that the IGF-I receptor is a physiological target for p53 in osteosarcoma cells. Furthermore, data supporting an interaction between p53 and Sp1 in the regulation of the promoter activity of IGF-IR are presented.
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PMID:p53 regulates insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1. 949 43

With the aim of identifying innovative therapeutic strategies for osteosarcoma patients who are refractory to conventional chemotherapy, we analyzed the in vitro effects of the blockage of autocrine circuits. Since the insulin-like growth factor-I receptor (IGF-IR)-mediated loop is relevant to the growth of osteosarcoma, we analyzed the activity of the IGF-IR-blocking antibody alphaIR3 in both sensitive and multidrug-resistant osteosarcoma cell lines. Only limited effects, however, were observed, suggesting the simultaneous existence of other autocrine circuits. Indeed, in a representative panel of 12 human osteosarcoma cell lines, in addition to the IGF-IR-mediated circuit, we demonstrated also a loop mediated by epidermal growth factor receptor as well as the presence of nerve growth factor, low-affinity nerve growth factor receptor as well as tyrosine receptor kinase A in the great majority of osteosarcomas. Therapies based on the inhibition of single circuits may have only limited effects in osteosarcoma, whereas the use of suramin, a drug which, besides other activities, non-selectively interferes with the binding of growth factors to their receptors, appears as a promising alternative, in both sensitive and drug-resistant osteosarcoma cells.
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PMID:Redundancy of autocrine loops in human osteosarcoma cells. 993 60

Insulin-like growth factor-I exerts potent mitogenic effects through the type I IGF receptor, a member of the insulin receptor family, and exhibits at the same time some insulin-like metabolic activities. We have questioned whether IGF-I presents moreover a modulatory effect upon programmed cell death (PCD)(apoptosis) in serum-deprived human osteosarcoma U-2 OS cells, a cell line synthesizing IGF-II and exhibiting an increased DNA synthesis following treatment with IGF-I. U-2 OS cells were cultured in a medium containing 0.8% FCS and growth arrest was induced by transfer to serum-free growth conditions. PCD was measured using a commercially available DNA degradation ELISA while viable cell numbers were counted microscopically after trypan exclusion to estimate net proliferative activity. Following serum withdrawal for 24 hrs., the level of PCD in U-2 OS cells was increased six-fold while cell number was reduced by approximately 35% compared to cells grown in the presence of 15% serum. Incubation with recombinant human IGF-I for 24 hrs. caused a dose-dependent inhibition of the level of programmed cell death. Co-incubation with an IGF-I receptor monoclonal antibody (alphaIR3) dose-dependently blocked the effects of 10 ng/ml IGF-I on PCD, with an ED50 of 1-10 ng/ml of alphaIR3 immunoglobulin. Conversely IGF-1 provoked a significant cell number increase, an effect blocked by addition of alphaIR3. The addition of an inhibitor of caspase 1 (ICE) had little effect on PCD but resulted in a net increase in the number of viable cells. In summary, IGF-I treatment of U-2 OS cells at the same time inhibits the induced programmed cell death and increases the cell number, effects which are blocked by addition of IGF-I receptor antibodies. These data support the hypothesis that IGF-I affects cells in a dual way, both by enhancing proliferative responses and by suppressing programmed cell death. The differential response between PCD and cell number to ICE inhibitors suggests the existence of independent control systems for these processes although the role of IGF-I in this study has yet to be determined.
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PMID:Insulin-like growth factor-I inhibits the progression of human U-2 OS osteosarcoma cells towards programmed cell death through interaction with the IGF-I receptor. 1072 73

This study investigated the ability of normal human osteoblasts (hOb) and osteogenic sarcoma cells (MG-63 and SaOS2) to produce gelatinases and undergo modulation by interleukin 1beta (IL-1beta), interleukin 6 (IL-6), oncostatin M (OSM), leukaemia inhibitory factor (LIF), growth hormone (GH) and insulin-like growth factor-I (IGF-I). Gelatinase activities were determined by zymogaphy, and a quantitative analysis was performed by ELISA. The MMP-2 activities of the three cell lines were significantly increased in the presence of IL-1beta and IL-6, but no modulation of MMP-2 activities was observed in the presence of OSM, LIF and GH. IGF-I increased the activity released by SaOS2 and hOb, but no modulation was detectable in MG-63 cell conditioned medium. An upmodulation of pro-MMP-2 secretion by SaOS2 and hOb was observed for all soluble factors used, whereas an upmodulation of pro-MMP-2 secretion by MG-63 was observed only in the presence of IL-1beta, IL-6 and IGF-I. Thus, osteoblastic cells modulated by cytokines can be involved in bone resorption as a result of the protease activities released.
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PMID:Modulation by soluble factors of gelatinase activities released by osteoblastic cells. 1105 27

The insulin-like growth factor-I receptor (IGF-l-R) plays a critical role in normal and pathological growth processes. The expression of the IGF-l-R gene is regulated by various stimuli, including hormones and growth factors. We have investigated the molecular mechanisms by which two inhibitory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), regulate IGF-l-R gene expression. TNF-alpha and IFN-gamma reduced the proliferation rates of the osteogenic sarcoma cell line, Saos-2, and the human salivary gland cell line, HSG, in a dose- and time-dependent fashion. This effect was associated with significant reductions in the levels of IGF-l-R mRNA and protein, and with inhibition of IGF-l-R promoter activity, suggesting that TNF-alpha and IFN-gamma affect IGF-l-R gene expression at the transcriptional level. In addition, TNF-alpha significantly decreased IGF-l-R mRNA stability. Combined cytokine treatment inhibited cellular proliferation and promoter activity in an additive manner. Taken together, these results suggest that a novel potential mechanism by which TNF-alpha and IFN-gamma affect cellular proliferation involves suppression of IGF-l-R promoter activity, as well as destabilization of IGF-l-R transcripts.
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PMID:Regulation of insulin-like growth factor-I receptor gene expression by tumor necrosis factor-alpha and interferon-gamma. 1136 37


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